Alzheimer's disease (AD) is a widespread cognitive disease characterized by neurodegeneration, agglomeration of β-Amyloid (Aβ) protein plaques around neurons and within cerebral vasculature, and neurofibrilliary tangles in the brain. Extensive studies indicate Aβ peptide generation and plaque aggregation are key pathological events in the development of AD. The studies evidence Aβ peptides are neurotoxic, as they are reported mediators of apoptosis, inflammation, and oxidative stress. For this reason, some of the earliest proposed therapeutic strategies entail the prevention or elimination of these Aβ peptides and subsequent deposits.
Aβ peptides are produced via the amyloidogenic pathway of amyloid precursor protein (APP) proteolysis, which involves the concerted effort of β and γ-secretases. Initially, β-secretase (BACE) cleaves APP, creating an Aβ-containing carboxyl-terminal fragment known as β-C-terminal fragment (β-CTF), or C99 and an amino-terminal, soluble APP-β (sAPP-β) fragment, which is released extracellularly. Intracellularly, the β-CTF fragment is then cleaved by a multi-protein γ-secretase complex, resulting in generation of the Aβ peptide and a smaller γ-CTF, also known as C57. While both cleavage events are essential to the formation of the peptide, it is the γ-secretase cleavage that determines which of the two major forms of the peptide (Aβ1-40, 42) will be generated and, consequently, the peptide's ability to aggregate and the rate at which it is deposited. Thus, one clear potential therapeutic target for AD has been γ-secretase.
Notch signaling pathways are important in cellular development and dysregulation is linked to tumorigenesis. Intracellular γ-secretase processes Notch pathway receptors. Despite the potential toxicity involving possible disruption of Notch signaling and intracellular accumulation of β-CTFs, γ-secretase inhibition remains a viable anti-amyloidogenic strategy. Novel γ-secretase inhibitors (GSI) significantly reduce Aβ production both in vitro and in vivo, initial testing of GSIs has indicated the GSIs improve cognitive functioning in a transgenic mouse model of AD (Tg2576). These finding have functioned to further the vigorous search for potential candidate GSIs. Glycogen synthase kinase 3 (GSK-3) is a tonically active serine/threonine kinase, which has been implicated in several disorders of the CNS. With regard to AD, both isoforms of GSK-3 (α and β) have been found to directly phosphorylate tau on residues specific to hyperphosphorylated paired helical filaments (PHFs), GSK-3β has been shown to phosphorylate APP and to contribute to Aβ mediated neurotoxicity, and GSK-3β has been found to phosphorylate PS1, which may act as a docking site for subsequent tau phosphorylation. Therefore, GSK-3 inhibitors are especially attractive as they may not only oppose Aβ generation but also neurofibrillary tangle (NFT) formation. Moreover, Phiel and colleagues (2003) reported that inhibition of the GSK-3α isoform may regulate γ-secretase cleavage of APP in a substrate-specific manner. Accordingly, this selective inhibition of GSK-3 might provide the maximal therapeutic benefit while reducing the potential for toxic side-effects.